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TitleDistinct associations of pioneer factor Ascl1-E12a with nucleosomes drive changes in cell fate.
Journal, issue, pagesMol Cell, Year 2026
Publish dateJun 12, 2026
AuthorsBing-Rui Zhou / Edgar Luzete-Monteiro / Jingchao Zhang / Naomi Takenaka / Hsin-Yao Tang / Meilin Fernandez Garcia / Mariel Coradin / Megan Frederick / Greg Donahue / Benjamin Garcia / Yawen Bai / Kenneth S Zaret /
PubMed AbstractUnderstanding how pioneer transcription factors target nucleosomal DNA and initiate chromatin accessibility reveals the earliest events in cell fate changes. We integrated structural, biochemical, ...Understanding how pioneer transcription factors target nucleosomal DNA and initiate chromatin accessibility reveals the earliest events in cell fate changes. We integrated structural, biochemical, and genomic approaches to assess how the pioneer factor Ascl1-E12a heterodimer perturbs nucleosomes in vitro and in vivo to induce a neural cell fate. Two Ascl1-E12a heterodimers shift and unwrap 15 bp of nucleosomal DNA in a stepwise manner while eliciting solvent exchanges within the octamer. Nucleosome binding, but not free DNA binding, by Ascl1-E12a is enhanced by two types of associations with the nucleosome that differentially affect the kinetics of DNA unwrapping and shifting. Nucleosome association mutants of Ascl1 perturb chromatin opening on linker histone-compacted nucleosome arrays-independent of nucleosome remodelers-and targeting of closed chromatin in vivo, with consequent deficiencies in cellular reprogramming. Our findings establish that distinct associations with nucleosomes are essential for the pioneer factor Ascl1 to overcome chromatin barriers to reprogram cell fate.
External linksMol Cell / PubMed:42285106
MethodsEM (single particle)
Resolution2.6 - 7.33 Å
Structure data

42040

8u9s

EMDB-42040, PDB-8u9s:
Cryo-EM structure of NRCAM nucleosome aided by scFv
Method: EM (single particle) / Resolution: 2.6 Å

42089

8ubi

EMDB-42089, PDB-8ubi:
Cryo-EM structure of NRCAM nucleosome aided by scFv (Class_A)
Method: EM (single particle) / Resolution: 2.8 Å

42090

8ubj

EMDB-42090, PDB-8ubj:
Cryo-EM structure of NRCAM nucleosome aided by scFv (3D Flex map)
Method: EM (single particle) / Resolution: 2.8 Å

42091

8ubk

EMDB-42091, PDB-8ubk:
Cryo-EM structure of Ascl1/E12a in complex with NRCAM nucleosome
Method: EM (single particle) / Resolution: 2.6 Å

EMDB-42092: Cryo-EM structure of Ascl1/E12a in complex with NRCAM nucleosome (Local Map 1)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-42093: Cryo-EM structure of Ascl1/E12a in complex with NRCAM nucleosome (Local Map 2)
Method: EM (single particle) / Resolution: 3.8 Å

42094

8ubl

EMDB-42094, PDB-8ubl:
Cryo-EM structure of Ascl1/E12a in complex with NRCAM nucleosome (3D Flex map)
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-75506: Cryo-EM map of Ascl1-E12a in complex with NRCAM nucleosome without scFv
Method: EM (single particle) / Resolution: 7.33 Å

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsNUCLEAR PROTEIN / nucleosome / pioneer transcription factors / DNA binding proteins / transcription

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